Current disease management
If left untreated, Wilson Disease is fatal. Copper accumulation cannot be controlled by a low copper diet so all patients diagnosed with Wilson Disease require life-long therapy for their disease, irrespective of type and severity of symptoms.
Treatment goals in Wilson Disease are centered on compensating for impaired copper metabolism, reducing toxic free copper & maintaining normal copper levels to improve the patients’ symptoms. With current treatments, improving symptoms can take several years and more than a third of patients presenting with neurologic symptoms show no improvement after several years of treatment.
Pharmaceutical products available today for the management of Wilson Disease were introduced several decades ago, and act either on copper excretion or uptake:
Penicillamine and trientine, which are also called general chelators, were introduced in the 1950s and 1960s and are recommended as initial treatment of symptomatic patients with Wilson Disease or those with active disease. They reduce the body’s copper levels by increasing copper excretion via urine. These compounds are non-specific to copper and also bind to other important metals such as iron and zinc.
Despite being standard of care, many patients receiving chelators develop side effects, some very serious, which can cause up to 30 % of patients to discontinue treatment. Penicillamine is associated with many side effects, including fever, lupus-like reaction, bone marrow suppression, nephrotic syndrome, elastosis perforans serpingosa that is a type of skin degeneration or hepatotoxicity, and many patients poorly tolerate this medication. Despite very limited data is available, trientine is perceived to be better tolerated, however nephrotic syndrome and aplastic anemia may still occur.In addition, approximately 25% of patients initiated on penicillamine and trientine experience a drug-induced neurological worsening during the initial phase of treatment. The presumed mechanism behind this worsening is a rapid mobilization of copper from the liver leading to high level of free-copper in the blood. Up to 50% of patients who experience neurological worsening never recover to pretreatment level and may be seriously disabled.
Chelators are administered as oral capsules 2-4 times per day on an empty stomach at least one hour before or two hours after meals, and at least one hour before or after any other pharmaceutical product or milk.
Zinc reduces dietary uptake of copper in the gut and the copper instead passes through the intestines and is excreted in the feces. Zinc is recommended as an alternative to chelator therapy for 1st line treatment of asymptomatic or pre-symptomatic patients. But because of its slow acting (6-12 months) during which time the disease can progress, zinc is generally reserved for maintenance therapy. Zinc has been shown to be less effective than chelating agents.
One of the relatively common side effect of zinc is gastric irritation. Zinc is administered as oral capsules up to 5 times per day on an empty stomach at least one hour before or two to three hours after meals.
- Liver transplant
In severe cases where liver disease progresses to organ failure, liver transplant may be necessary. Published data suggest that 6-12% of liver transplants are due to the consequences of Wilson Disease. Liver transplantation is indicated for the approximately 5% of Wilson Disease patients with acute liver failure as the first presentation of disease, most commonly in the second decade of life, or those who present with end-stage liver disease and severe hepatic insufficiency, most commonly in the third and fourth decades.
Penicillamine, trientine and zinc are approved in the USA, whereas in the EU only zinc (Wilzin) is approved in all of the EU member states. Access to penicillamine and trientine varies considerably among the European countries.